Non-small cell lung cancer (NSCLC) is a devastating illness that will affect approximately 172,570 people in the United States in 2005 and for whom 5 year survival remains dismal at approximately 15%. The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in promoting cell cycle progression and cell proliferation, and is frequently up-regulated in many cancers including NSCLC. Rapamycin and its analogues, such as RAD001, are highly specific inhibitors of mTOR and are now in phase I - II oncology clinical trials. Akt, a survival protein frequently activated due to ras mutations and overexpression of growth factor receptors in human NSCLC, positively regulates mTOR signaling via tuberous sclerosis complex 2(TSC2), whereas LKB1, a tumor suppressor gene, mutates with high frequency in NSCLC, negatively regulates mTOR signaling. Thus, both Akt activation and LKB1 mutation may impact cell sensitivity or response to mTOR inhibitors. In this proposal, we attempt to determine the prognostic values of key proteins (p-Akt, p-mTOR, p-70S6K, p-4E-BP1, p-S6) in the mTOR axis in non-small cell lung cancer by obtaining tissue from the NATCH (Nee-Adjuvant Jrial of Chemotherapy Hope) and integrating these biomarkers together with others obtained from Projects 2-5 into a molecular prognostic model for operable NSCLC. We will then cross validate that model in tissue samples from patients treated surgically for NSCLC at the Emory-Winship Cancer Institute Programs. Having confirmed the importance of these biomarkers in human lung cancer tissue, we will then use these proteins as biomarkers in a series of novel translational clinical trials evaluating the mTOR inhibitor as preoperative biochemical therapy in resectable NSCLC and subsequently in combination therapy with docetaxel in metastatic disease. By accomplishing these aims, we can test our hypothesis that aberrant activation of mTOR signaling due to frequent Akt activation and LKB1 mutations in NSCLC impacts patient prognosis and serves as opportune target for effective treatment of NSCLC using mTOR inhibitors and their combinations with chemotherapy.